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E-cadherin expression is correlated with focal adhesion kinase inhibitor resistance in Merlin-negative malignant mesothelioma cells

Oncogene volume 36, pages 5522–5531 (2017)Cite this article

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Abstract

Malignant mesothelioma (MM) is an aggressive tumor commonly caused by asbestos exposure after a long latency. Focal adhesion kinase (FAK) inhibitors inhibit the cell growth of Merlin-deficient MM cells; however, their clinical efficacy has not been clearly determined. The aim of this study was to evaluate the growth inhibitory effect of the FAK inhibitor VS-4718 on MM cell lines and identify biomarkers for its efficacy. Although most Merlin-deficient cell lines were sensitive to VS-4718 compared with control MeT-5A cells, a subset of these cell lines exhibited resistance to this drug. Microarray and qRT–PCR analyses using RNA isolated from Merlin-deficient MM cell lines revealed a significant correlation between E-cadherin mRNA levels and VS-4718 resistance. Merlin- and E-cadherin-negative Y-MESO-22 cells underwent apoptosis upon treatment with a low concentration of VS-4718, whereas Merlin-negative, E-cadherin-positive Y-MESO-9 cells did not undergo VS-4718-induced apoptosis. Furthermore, E-cadherin knockdown in Merlin-negative MM cells significantly sensitized cells to VS-4718 and induced apoptotic cell death upon VS-4718 treatment. Together, our results suggest that E-cadherin serves as a predictive biomarker for molecular target therapy with FAK inhibitors for patients with mesothelioma and that its expression endows MM cells with resistance to FAK inhibitors.

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Acknowledgements

This work was supported by JSPS KAKENHI (Grant Numbers JP25290053 and JP16H04706), the Takeda Science Foundation, a Research Grant from the Princess Takamatsu Cancer Research Fund (14-24617), Project Mirai Cancer Research Grants, and P-DIRECT. We thank Dr Adi F Gazdar for the cell lines, Dr Hideki Murakami for his technical support during gene expression profiling, and Miwako Nishizawa for her excellent technical assistance. We gratefully thank Dr Hirotaka Osada for the study design and his careful supervision of the data (Dr Osada was a member of our lab and passed away on 23 August 2016).

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Authors and Affiliations

  1. Division of Molecular Oncology, Aichi Cancer Center Research Institute, Nagoya, Japan

    T Kato, T Sato & Y Sekido

  2. Department of Thoracic Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan

    T Kato & K Yokoi

  3. Department of Cancer Genetics, Program in Function Construction Medicine, Nagoya, Japan

    Y Sekido

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Correspondence to Y Sekido.

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Kato, T., Sato, T., Yokoi, K. et al. E-cadherin expression is correlated with focal adhesion kinase inhibitor resistance in Merlin-negative malignant mesothelioma cells. Oncogene 36, 5522–5531 (2017). https://doi.org/10.1038/onc.2017.147

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